When chronic administration of a pharmaceutically-active agent is required, vascular delivery via an external infusion pump, implantable infusion pump (IIP) or other vascular access device may be the dispensing means of choice. For example, IIP delivery may be preferred when either (a) the oral bioavailability of the agent is low (i.e., the drug is destroyed by gastrointestinal acids and enzymes or is not absorbed by the intestinal wall); (b) the therapeutic index of the drug is small (i.e., the dosage range between ineffectivity and toxicity is narrOw); (c) the in vivo half-life of the drug is short; or (d) the site of the delivery is important.
To realize the potential benefits of drug delivery by IIP, pharmaceutical preparations need to be designed to retain stability under environmental conditions not ordinarily encountered during storage and administration by conventional methods such as oral ingestion or parenteralinjection. These conditions include the surface properties of the materials used in IIP construction, the fluid dynamic variables that infusates are exposed to during transport through the devices, and the nature and amounts of the various gasses and fluids which permeate the device from the recipient's body.
Furthermore, drug formulations designed for parenteral delivery are generally designed for storage at temperatures other than physiological temperatures. Therefore, it is not unusual for a drug preparation, in the form that it is dispensed for conventional administration, to be incompatible with a particular pump. In such cases, either the pump, the drug molecule or the drug formulation must be modified to achieve reliable function of the IIP without compromising drug bioavailability.
A number Of pharmaceutical agents that might be delivered advantageously by implantable drug infusion pump or other vascular access means are insoluble in aqueous solutions. Some agents of this type are soluble in alcohols but alcohols may be unsuitable for use with certain types of infusion devices because of their carrying capacity for dissolved gasses, which can be rapidly released when the drug is delivered in vivo. For example, the vapor pressure-driven IIP disclosed by Blackshear et al. (U.S. Pat. No. 3,731,681) pumps a solution of a drug through 0.09 mm inner diameter capillary flow restrictors of lengths ranging from about 15 cm to more than 30 meters. Passage of the drug-containing infusate through the capillary catheter is accompanied by a pressure drop of approximately 20 kg/cm.sup.2 due to the difference between drug reservoir pressure (23 kg/cm.sup.2) and the venous or arterial blood pressure at the catheter tip. This pressure drop can be accompanied by the release of air bubbles from the infusates. This phenomenon, called outgassing, is determined by the vapor pressure and dissolved gas capacity of the solvent.
In the case of aqueous solutions, outgassing ordinarily does not result in air bubbles stopping the Blackshear et al. pump. However, if a pump is loaded with ethanol, which has seven times the capacity for air as does water under identical conditions of temperature and pressure, gas bubbles can form in the capillary flow restrictor. These bubbles collectively exert sufficient resistance to stop pump flow after less than 50 ml of infusate delivery.
Cyclosporin is one example of an important drug that is difficult to deliver via parenteral infusion because of its hydrophobicity. It is a powerful immunosuppressive drug that has improved graft survival in organ transplant recipients. In addition to its utility in organ transplantation, it may be effective in treating auto-immune diseases. Based on successful laboratory animal research, clinical pilot studies are now underway to test its ability to combat multiple sclerosis, lupus erythematosis, and rheumatoid arthritis. It may also prove effective to bring about remission of juvenile onset diabetes if given immediately after onset. Cyclosporin is also effective against such parasitic diseases as malaria and schistosomiasis.
Despite its advantages, the therapeutic index of cyclosporin is narrow so that dosages must be regulated within precise limits. The major side effect of cyclosporin is nephrotoxicity in 15 to 30% of patients. Therefore, a need exists for solvent systems which are useful to prepare infusates for the delivery of cyclosporin and other hydrophobic drugs via IIP, external infusion pumps, or other vascular access devices.